The publications and the material used herein to illuminate the background of the invention and, in particular, cases to provide additional details respecting the practice, are incorporated by reference.
The use of drug delivery systems for the delivery of a therapeutically active agent, which systems provide for steady release of a therapeutically active agent to a patient's body at a controlled rate over a prolonged period of time in order to achieve a desired physiological or pharmacological effect, have proved beneficial in many therapeutic areas. A principal advantage of employing sustained-release compositions is that many therapeutically active agents would otherwise be rapidly metabolised or cleared from the patient's body, thus necessitating frequent administration of the therapeutically active agent to maintain a therapeutically effective concentration.
A problem often faced in controlling the release of the therapeutically active agent by using a slow releasing preparation is initial burst, i.e. the release of a relatively large amount of the therapeutically active agent right after the preparation has been administered or inserted to the patient. If such an initial burst occurs, the concentration of the therapeutically active agent in the blood may exceed the permissible upper limit, which may be dangerous to the patient. Initial burst can be prevented to a certain extent by selecting the form of the therapeutically active agent and the releasing material, but a basic solution for preventing initial burst has been the subject of extensive studies. On the other hand, the concentration of a therapeutically active agent in a preparation should be as high as possible in order to achieve slow release of the therapeutically active agent over a long period of time and to be able to maintain a moderate size of the preparation.
The initial burst may be decreased or avoided by modifying the physical state of the active agent. The therapeutically active agent can be incorporated into a controlled release agent, such as polymer microspheres, which steadily or intermittently release the therapeutically active agent. Examples of suitable controlled release components include microstructures, such as microparticles, nanoparticles, cyclodextrins, microcapsules, micelles and liposomes. The controlled release component may also include macrostructures. Suitable controlled release components also include salts of the therapeutically active agent and complexes or conjugates in which the therapeutically active agent is operatively associated with a carrier molecule.
For the liquid delivery compositions, which typically include a biodegradable and/or bioerodable polymer or copolymer dissolved in a non-toxic organic solvent, the additional time required to release the therapeutically active agent from the controlled release component will enable the formulation to solidify into a solid implant without the initial loss of a substantial amount of the therapeutically active agent. Once formed into a solid matrix, the permeation of the therapeutically active agent is based on the rates the therapeutically active agent is released from the controlled release component and from the implant matrix. The second mode is governed by the rate of biodegradation and/or bioerosion of the implant material.
On the other hand, in making the polymer microspheres the controlled release components, such as cyclodextrin, also serve as a buffer and reduce denaturing of a sensitive therapeutically active agent, e.g. when the microspheres are compressed into pellets. The buffers usually dissolve more quickly than the polymer and hereby facilitate the release of the therapeutically active agent by creating tunnels in the microspheres Inclusion of the controlled release components can therefore also lead to an initial burst of drug release after implantation.
A variety of methods for achieving low initial burst of formulations of therapeutically active agents have been described in the literature. Such methods have mainly been focused in injection delivery systems, such as microparticles, liquid polymer compositions and gel compositions.
International Patent Application WO 95/27481 A1 is related to liquid polymer compositions that are useful for the delivery of therapeutically active agents in vivo and permit the initial burst to be controlled more effectively than previously possible. When a liquid delivery system including a biodegradable polymer and a therapeutically active agent dissolved in a water-soluble solvent comes into contact with an aqueous medium, such as a body fluid, the solvent dissipates or diffuses into the aqueous medium. As the polymer precipitates or coagulates to form a solid matrix, the active agent is trapped or encapsulated throughout the polymeric matrix. The release of the active agent then follows the general rules for the dissolution or diffusion of a therapeutically active agent from within a polymeric matrix. The formation of the solid matrix from the liquid delivery system is, however, not instantaneous but typically occurs over a period of several hours. During this initial period, the rate of diffusion of the active agent may be much more rapid than the rate of release that occurs from the subsequently formed solid matrix. The initial burst can be decreased by incorporating the active agent into a controlled release component and combining the controlled release component with the liquid polymer systems described for example in U.S. Pat. Nos. 4,938,763, 5,278,201 and 5,278,202.
International Patent Application WO 01/08717 A1 is related to implantable devices, where the therapeutically active agent is incorporated into a controlled release agent, such as polymer microspheres, which steadily or intermittently release the therapeutically active agent. Various polymers can be used for encapsulating therapeutically active agents in microspheres. Preferably, the polymers are biocompatible and degradable when placed within human tissue. In the preparation of the microspheres, buffers, such as sucrose and cyclodextrin, can be added. Inclusion of buffers is, however shown to lead to an initial burst of the active agent during, e.g., the first 24 hours after implantation.
International Patent Application WO 96/01626 A1 is related to a transdermal system comprising a reservoir with the therapeutically active agent in ionized form, a pH adjusting agent and a cyclic polysaccharide for improving the solubility of the therapeutic agent in the buffer solution. The polysaccharide may be selected from a group consisting of cyclodextrin or a derivative thereof and a cyclodextrin polymer. The reservoir wall comprises a polymer, which is substantially impermeable to the ionized form or the inclusion complex of the therapeutically active agent, but is permeable to water and to the unionized form of the therapeutically active agent. The therapeutically active agent is able to penetrate through the reservoir wall only when the system is applied to the skin and water penetrates through the reservoir wall into the core. During these initial stages the release rate of the therapeutically active agent slowly increases until the concentration of the therapeutically active agent in the reservoir wall reaches steady-state levels. The delay before steady levels are achieved in plasma can be avoided by loading the reservoir wall of a single core reservoir system with the therapeutically active agent to give a priming dose of the therapeutically active agent. The loading of the reservoir wall can cause an initial burst. The magnitude of the burst or delay in the release of the therapeutically active agent can be modified by varying the amount of the therapeutically active agent that is loaded.
A publication of J Biomater Sci Polym Ed. 1994;5(4):339-51 describes controlled release systems prepared from biodegradable microparticles of poly(lactic acid-co-glycolic acid) containing beta-estradiol in the presence or absence of silicone. The release behaviour of beta-estradiol from free microparticles as well as from microparticles embedded within a silicone matrix is compared with the release behaviour shown by non-encapsulated beta-estradiol within a silicone matrix. It was found that incorporating biodegradable microparticles within a silicone matrix lessens the initial burst of release often seen with these types of formulations and provides a controlled release of therapeutically active agent.
The above applications concentrate on injectable formulations, wherein the controlled release or regulating material and the therapeutically active agent are located in the same phase of the delivery system.
Document US 2002/0161352 presents a vaginal ring preparation comprising a tubular base of an inert rubber, a first layer on top of it comprising a drug, a surfactant and a dispersing agent as well as a second layer of silicone rubber encapsulating said first layer on the tubular base. The dispersing agent may be for example R-type or B-type cyclodextrin. Thus this document does not disclose a core-membrane-structure wherein the therapeutically active agent is comprised in the core.
The initial burst effect, i.e. the amount of therapeutically active agent typically released in the first 24-48 hours, is non-efficient by resulting in the loss or release of a relatively large amount of the therapeutically active agent. If the therapeutically active agent is not well tolerated, this initial burst is likely to lead to side effects and may cause damage to the adjacent tissues. In any of the above cases, these effects may prohibit the use of that certain formulation, if the burst effect cannot be minimized.
The development of delivery systems with reduced or eliminated initial burst effect would represent a significant advancement. The efficiency of such systems would be improved, since a greater percentage of the active agent would remain in the device for sustained release and not be lost during the initial burst. The possibility of side effects would be reduced. There is, therefore, a continuing need for controlled release systems that will facilitate the sustained release of a therapeutically active agent in a patient's body without creating an initial burst of therapeutically active agent.